Abstract:
Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1AMPK-mediated phosphorylation of Sch9S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1AMPK and Sch9S6K. Hence, the DDR and repair pathways in aging cells are influenced by the metabolic tuning of opposing AMPK and TORC1 networks and by PP2A activity. Specific Sch9S6K phospho-isoforms control DDR and NER efficiency, specifically during aging.
摘要:
UV诱导的DNA损伤的存活依赖于核苷酸切除修复(NER)和Mec1ATRDNA损伤应答(DDR)。我们研究了衰老细胞中的DDR和NER,发现旧细胞难以修复DNA并激活Mec1ATR。我们采用药理学和遗传学方法来拯救衰老过程中的DDR和NER。激活Snf1AMPK救援DDR功能的条件,但不是NER,而TORC1-Sch9S6K轴的抑制通过调节PP2A活性恢复NER并增强DDR,特别是在老化细胞中。年龄相关的修复缺陷取决于Snf1AMPK介导的Sch9S6K在Ser160和Ser163上的磷酸化。旧细胞中的PP2A活性对DDR有害,并通过调节Snf1AMPK和Sch9S6K影响NER。因此,衰老细胞中的DDR和修复途径受到相反的AMPK和TORC1网络的代谢调节以及PP2A活性的影响。特定的Sch9S6K磷酸亚型控制DDR和NER效率,特别是在衰老过程中。